22-41178850-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001429.4(EP300):c.7139C>T(p.Pro2380Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000681 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2380S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2O:1

Conservation

PhyloP100: 4.46

Publications

1 publications found

Variant links:

Genes affected

EP300 (HGNC:3373): (E1A binding protein p300) This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]

EP300 links:

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

EP300-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23590821).

BP6

Variant 22-41178850-C-T is Benign according to our data. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178850-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 134055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EP300	NM_001429.4 link	c.7139C>T	p.Pro2380Leu	missense_variant	Exon 31 of 31	ENST00000263253.9	NP_001420.2	Q09472Q7Z6C1
EP300	NM_001362843.2 link	c.7061C>T	p.Pro2354Leu	missense_variant	Exon 30 of 30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9 link	c.7139C>T	p.Pro2380Leu	missense_variant	Exon 31 of 31	1	NM_001429.4	ENSP00000263253.7		Q09472

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251438

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

EP300-related disorder

Uncertain:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EP300 c.7139C>T variant is predicted to result in the amino acid substitution p.Pro2380Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Benign:1

Jan 03, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.028

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.7

PhyloP100

4.5

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.033

Polyphen

0.099

Vest4

0.48

MVP

0.84

ClinPred

0.23

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.34

gMVP

0.41

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over